Efficient cobalt(ii) phthalocyanine-catalyzed reduction of flavones with sodium borohydride

Article abstract of DOI:10.1039/b912928f

Efficient and facile reductions of flavones with sodium borohydride (NaBH₄) catalyzed by cobalt(ii) phthalocyanines afford cis-flavan-4-ols in 89-97% yields.

Full text of DOI:10.1039/b912928f

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Efficient cobalt(II) phthalocyanine-catalyzed reduction of flavones
with sodium borohydridew
Pratibha Kumari, Poonam and Shive M. S. Chauhan*
Received (in Cambridge, UK) 30th June 2009, Accepted 8th September 2009
First published as an Advance Article on the web 23rd September 2009
DOI: 10.1039/b912928f
Efficient and facile reductions of flavones with sodium
borohydride (NaBH4) catalyzed by cobalt(II) phthalocyanines
afford cis-flavan-4-ols in 89–97% yields.
Table 1 Reduction of 1a to 4a with NaBH4 catalyzed by 3a in
methanol under different reaction conditions
Substrate :
Conv. Yield
Entry System
catalyst : NaBH4 Time/h (%)a (%)b
Flavonoids represent an important class of naturally occurring
compounds that are responsible for flavors in foods, and
colour in fruits, vegetables and flowers. Flavones are studied
extensively for their antitumor,1 fungicidal,2 antifeedant,3
antioxidizing,4 bactericidal5 and analgesic properties.6 On
ingestion, flavonoids are known to undergo oxidative
metabolic degradations,7 and not much is known about their
reductive biotransformations.8 Recently, in vitro reductions of
flavones to flavan-4-ols have seen growing interest owing to
their antioxidizing, bactericidal and fungicidal activities.9
Lithium aluminium hydride,10 NaBH4/Lewis acid,11
NaBH4/excimer laser12 and nickel boride13 are known to
reduce a few flavones from previous reports. However, slower
reaction rates and low yields were some of the drawbacks
associated with these methods.
1
2
3
4
5
6
7
8
1a/3a/NaBH4 1 : 0 : 16
24
2
2
2
1
2
2
2
0
92
89
72
26
35
73
98
0
89
87
70
1a/3a/NaBH4 10 : 1 : 80
1a/3a/NaBH4 50 : 1 : 400
1a/3a/NaBH4 100 : 1 : 800
1a/3a/NaBH4 10 : 1 : 10
1a/3a/NaBH4 10 : 1 : 20
1a/3a/NaBH4 10 : 1 : 40
1a/3a/NaBH4 10 : 1 : 160
Tracec
33
69
93d
a
b
Based on substrate 1a. Isolated yields. Flavanone (6a) was isolated
c
d
in 20% yield. Some unidentified products were also observed.
Scheme 2
We have developed many catalytic systems using
metalloporphyrins14 and metallophthalocyanines (MPcs)15
for various oxidative and reductive chemical transformations.
In comparison to the application of MPcs as oxidative
catalysts, their ability to reduce has received considerably less
attention in organic synthesis.16 As an ongoing effort to
emphasize the role of MPcs as reduction-promoting
catalysts,15,17 herein, we report an efficient reduction of
flavones 1–2 using NaBH4 in the presence of a series of MPcs,
3a–3g (Scheme 1).
selectively in 89% yield (Table 1, entry 2) (for configuration
determination see the ESIw). The catalytic activity of 3a was
examined by varying its molar ratio in reactions (Table 1,
entries 2–4). A noticeable change in the yield of 4a was
observed on reducing the molar ratio of 1a : 3a to 100 : 1.
To further optimise the reaction conditions and to investigate
the reaction intermediate(s), the reduction of 1a was carried
out using different molar ratios of NaBH4. Interestingly, the
reaction of 1a with an equimolar amount of NaBH4 yielded
flavanone (6a) (see the ESIw), which was then reduced to 4a
with a higher molar ratio of NaBH4 (Scheme 2 and Table 1,
entries 5–8). The above experiments suggest that the present
reductive system initially reduces the conjugated double bond
and then the carbonyl group. This fact is further supported
by the selective reduction of the double bond in methyl
3-(4-methylphenyl)prop-2-enoate under the same conditions
(see the ESIw). Additionally, the reaction of chalcone with
NaBH4 gave 1,3-diphenyl-2-propenol, and a similar reaction
in presence of 3a afforded 1,3-diphenyl-1-propanol,
justifying the chemoselective approach of the reductive system
(see the ESIw). The observations given in Table 1 revealed that
the reaction with a molar ratio of substrate : catalyst : NaBH4
of 10 : 1 : 160 gave the best result.
The reduction of flavone (1a) with NaBH4 in the absence of
MPcs 3a–3g did not yield flavan-4-ol, even after 24 h.
However, the same reaction in the presence of cobalt(II)
phthalocyanine (3a) gave the cis-form of flavan-4-ol (4a)
Scheme 1 Reduction of flavones 1–2.
The scope and limitations of the catalyst in the reaction
were investigated by employing a series of MPcs and metal
salts (Table 2). The change of the central metal ion of MPc
from Co to Ni and Fe resulted in lesser catalytic activities
(Table 2, entries 1 and 2). The nature of substituents attached
Department of Chemistry, University of Delhi, Delhi-110007, India.
E-mail: smschauhan@chemistry.du.ac.in; Fax: +91-11-27666605;
Tel: +91-11-27666845
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data for the products and complete
details about the reduction of flavones. See DOI: 10.1039/b912928f
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Table 2 Reduction of 1–2 to 4–5 with NaBH4 in methanol using
different catalystsa
Time/
h
Conv.
(%)b
Yield
(%)c
Entry Substrate Catalyst Product
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
3b
3c
3d
3e
3f
3g
CoCl2
NiCl2
FeCl3
3a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
3
3
4
2
3
3
5
5
6
3
3
3
24
3
64
56
83
77
42
97
56
60
34
96
93
94
0
61
50
82
75d
40e
95
49f,g
52f,h
28f,i
95
Fig. 1 UV-vis spectra of 3a (a) in methanol, (b) (b–i) on addition of
9
NaBH4 in methanol at an interval of 1 min.
10
11
12
13
14
3a
3a
3a
3a
90
92
reactions suggests that one hydrogen comes from methanol
and the source of another hydrogen is NaBH4 in the reduction
reactions. Furthermore, the UV-vis spectral studies of 3a on
addition of NaBH4 showed a new band at 464 nm, accompanied
by a red shift in the Q band from 662 to 705 nm (Fig. 1),
specifying the formation of [Co(I)Pc] (9), an intermediate in
the reaction.18 This is attributed to the tendency of MPcs to
take up electrons reversibly in the dz2 orbital of the central
metals.19 It is notable that insoluble MPc became soluble with
a specific change in colour when NaBH4 was added in the
reaction, supporting the involvement of the [M(I)Pc] reactive
species in the reduction.16c,20 Furthermore, a steady decrease
in the absorption intensity at 705 nm with the appearance
of new bands at 594 and 656 nm (Fig. 1) suggested the
transformation of 9 into hydridocobalt(III) phthalocyanine
(10) intermediate.22e The stability and rate of formation of 9
and 10 were found to be affected by changing the solvent from
methanol to propanol (see ESIw), justifying the role of the
solvent in reduction.
1d
1e/1f
2
4d
4e/4f
5
0j
98
97
a
Reaction conditions—substrate : catalyst : NaBH4 = 10 : 1 : 80.
b
c
Based on substrate 1a. Isolated yields. Partial decomposition of
d
e
the catalyst was observed. The yield of 4a improved to 55% when the
reaction was performed in methanol/dichloromethane (1 : 1, v/v),
although partial decomposition of the catalyst and the formation of a
f
red species was observed. The reaction mixture turned black
immediately on addition of NaBH4 and many unidentified products
g
were observed after the reaction. The black colour of the reaction
h
disappeared after 90 min. The black colour of the reaction persisted
i
even after completion of the reaction. The black colour of the
j
reaction disappeared after 2 h. The reaction remained unaffected
on increasing the amount of NaBH4 up to 160 equiv. vs. 3a and on
prolonging the reaction for 24 h.
to the MPc ring also affected the course of reduction (Table 2,
entries 3–6). After the reactions, the catalysts 3a–3g were
quantitatively recovered and can be reused without any loss
in catalytic activity. The use of metal salts as catalysts showed
quite poor activity (Table 2, entries 7–9). Moreover, these
catalysts decomposed after the reductions and could not be
reused.
The reduction of 1–2 is believed to proceed by the active
catalyst 9, which, being a supernucleophile,21 easily takes up a
proton from methanol to give the cobalt hydride complex 10
(Scheme 4). Homolytic cleavage of the H–Co bond, followed
by stepwise addition to the conjugated double bond of the
The flavones bearing various substituents at the C-40
position (1b–1d) were also reduced in good yields by the
present reductive system (Table 2, entries 10–12). However,
the presence of the electron donating –OH group at the C-3
position and the resulting increase in electron density around
the olefinic carbons in 1e renders it difficult to be reduced using
similar conditions, and the desired product was not formed
even after 24 h (Table 2, entry 13). Likewise, 1f remained
stable under the reaction conditions, mitigating the
pronounced effect of the –OH group on the course of reaction.
These findings justify that reduction of the double bond is
followed by reduction of the carbonyl group by the present
system.
ꢁ
hydrogen radical and then the Co(III)Pc species (insertion of
alkene into 10) gives 11. This addition is in accordance with
The reaction of 2 using NaBD4 in methanol and with
NaBH4 in CD3OD assisted understanding of the mechanism
of reduction (Scheme 3). The formation of 7 and 8 in the above
Scheme 3
Scheme 4 Proposed mechanism for the reduction of flavones (1–2).
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the catalysis by cobalt complexes22 and the structurally related
metalloporphyrins.23 The C–Co(III)Pc bond is reductively
cleaved by NaBH4 to yield 6, owing to the tendency of
alkylcobalt complexes to be dealkylated by nucleophiles.21 In
the same way, 6 is reduced by 10 regioselectively to afford 4
(Scheme 4). The stereospecificity of the reduction may be
dictated by the steric hindrance of the phenyl group during
the insertion of CQC and CQO into 10. After completion of
the reaction, Co(II)Pc regenerates by the aerobic oxidation of 9
and can be reused several times without any loss in its catalytic
activity.
13 J. M. Khurana and S. Chauhan, J. Chem. Res., Synop., 2002, 201.
14 (a) S. M. S. Chauhan and P. Kumari, Tetrahedron Lett., 2007, 48,
5035; (b) N. Jain, A. Kumar and S. M. S. Chauhan, Tetrahedron
Lett., 2005, 46, 2599; (c) S. M. S. Chauhan, A. S. Kandadai,
N. Jain and A. Kumar, Chem. Pharm. Bull., 2003, 51, 1345;
(d) S. M. S. Chauhan, B. Sahoo, P. P. Mohapatra, B. Kalra and
A. Gulati, Chem. Pharm. Bull., 2001, 49, 1232; (e) S. M. S.
Chauhan, S. A. Kandadai and B. Sahoo, Chem. Pharm. Bull.,
2001, 49, 1375; (f) S. M. S. Chauhan, J. Indian Chem. Soc., 1996,
73, 637; (g) S. M. S. Chauhan, B. Kalra and P. P. Mohapatra,
J. Mol. Catal. A: Chem., 1999, 137, 85; (h) S. M. S. Chauhan,
P. P. Mahapatra, K. V. Rao, B. Vijayaraghavan and S. P. Shahi,
Indian J. Heterocyl. Chem., 1996, 5, 181; (i) S. M. S. Chauhan,
B. Vijayaraghavan and K. V. Rao, Indian J. Chem. B, 1987, 26,
122; (j) S. M. S. Chauhan, S. A. Kandadai and A. Kumar,
Chem. Pharm. Bull., 2002, 50, 1421.
In conclusion, Co(II)Pc along with NaBH4 presents an
effective catalytic system to achieve selective reductions of
various flavones to cis-flavan-4-ols. The present method offers
various advantages such as high yield of products, shorter
reaction time, milder conditions, simple work-up procedure
and reusability of the catalyst.
15 S. M. S. Chauhan, A. Kumar and K. A. Srinivas, Chem. Commun.,
2003, 2348.
16 (a) H. Eckert, Angew. Chem., 1981, 93, 216; (b) H. Eckert and
Y. Kiesel, Synthesis, 1980, 947; (c) H. Eckert and Y. Kiesel, Angew.
Chem., 1981, 93, 477; (d) C. Brown, R. W. Marston, P. F. Quigley
and S. M. Roberts, J. Chem. Soc., Perkin Trans. 1, 2000, 1809;
(e) S. Prateeptongkum, I. Jovel, R. Jackstell, N. Vogl,
C. Weckbeckerb and M. Beller, Chem. Commun., 2009, 1990.
17 (a) S. M. S. Chauhan, S. Agarwal and P. Kumari, Synth. Commun.,
2007, 37, 2917; (b) S. M. S. Chauhan, P. Kumari and S. Agarwal,
Synthesis, 2007, 3713; (c) S. M. S. Chauhan, K. A. Srinivas,
P. K. Srivastava and B. Sahoo, J. Porphyrins Phthalocyanines,
2005, 29, 548; (d) S. M. S. Chauhan and P. Kumari, Tetrahedron,
2009, 65, 2518.
18 (a) P. Day, H. A. O. Hill and M. G. Price, J. Chem. Soc. (A), 1968,
90; (b) E. V. Kudrik, S. V. Makarov, A. Zahl and R. van Eldik,
Inorg. Chem., 2003, 42, 618; (c) J. Grodkowski, T. Dhanasekaran,
P. Neta, P. Hambright, B. S. Brunschwig, K. Shinozaki and
E. Fujita, J. Phys. Chem. A, 2000, 104, 11332; (d) I. Yilmaz,
S. Arslan, S. Guney and I. Becerik, Electrochim. Acta, 2007, 52,
6611.
The authors are grateful to the Council of Scientific and
Industrial Research, New Delhi, India for financial assistance.
Notes and references
1 (a) M. Cabrera, M. Simoens, G. Falchi, M. L. Lavaggi, O. E. Piro,
E. E. Castellano, A. Vidal, A. Azqueta, A. Monge, A. L. de Cerain,
G. Sagrera, G. Seoane, H. Cerecetto and M. Gonzalez, Bioorg.
Med. Chem., 2007, 15, 3356; (b) L. W. Wattenberg and J. L. Leong,
Cancer Res., 1970, 30, 1922.
2 O. Bozdag-Dundar, M. Ceylan-Unlusoy, N. Altanlar and
R. Ertan, Arzneim. Forsch., 2005, 55, 102.
3 M. Morimoto, K. Tanimoto, S. Nakano, T. Ozaki, A. Nakano and
K. Komai, J. Agric. Food Chem., 2003, 51, 389.
4 N. Cotelle, J. L. Bernier, J. P. Henichart, J. P. Catteau, E. Gaydou
and J. C. Wallet, Free Radical Biol. Med., 1992, 13, 211.
5 M. E. Ullah, M. Ayaz, Z. Hussain, A. Hasan, A. Sadiq, M. Riaz,
A. Malik, S. Hussain and M. I. Choudhary, Bioorg. Med. Chem.,
2006, 14, 4704.
6 P. Thirugnanasambantham, S. Viswanathan, S. Ramaswamy,
V. Krishnamurty, C. Mythirayee and L. Kameswaran, Clin. Exp.
Pharmacol. Physiol., 1993, 20, 59.
7 (a) R. R. Scheline, in Mammalian Metabolism of Plant Xenobiotics,
Academic Press, London, 1978; (b) L. A. Griffiths, in The
Flavonoids: Advances in Research, ed. J. B. Harborne and
T. J. Mabry, Chapman and Hall, London, 1982, p. 681;
(c) A. M. Hackett, in Plant Flavonoids in Biology and Medecine:
Biochemical, Pharmacological, and Structure-Activity Relationships,
ed. V. Cody, E. Middleton, Jr, J. B. Harbone and Alan R. Liss,
New York, 1986, p. 177; (d) J. Heilmann and I. Merfort, Pharmazie
in unserer Zeit, 1998, 27, 173; (e) T. Chan, G. Galati and
P. J. O’Brien, Chem.-Biol. Interact., 1999, 122, 15.
8 (a) S. R. Udupa and M. S. Chadha, Indian J. Biochem. Biophys.,
1981, 18, 142; (b) S. R. Udupa, A. Banerji and M. S. Chadha,
Tetrahedron Lett., 1968, 9, 4003; (c) D. Nikolic and R. B. van
Breemen, Drug Metab. Dispos., 2004, 32, 387; (d) E. Kostrzewa-
Suslow, J. Dmochowska-Gladysz, A. Bialonska, Z. Ciunik and
W. Rymowicz, J. Mol. Catal. B: Enzym., 2006, 39, 18.
9 (a) Z. Zhao, J. Jin, J. Ruan, C. Zhu, C. Lin, W. Fang and Y. Cai,
J. Nat. Prod., 2007, 70, 1683; (b) F. Spinelli, G. Costa,
J.-B. Speakman, W. Rademacher, H. Halbwirth and K. Stich,
Acta Horticulturae, 2006, 704, 239; (c) L. Dykes, L. W. Rooney,
R. D. Waniska and W. L. Rooney, J. Agric. Food Chem., 2005, 53,
6813; (d) F. Spinelli, J.-B. Speakman, W. Rademacher,
H. Halbwirth, K. Stich and G. Costa, Eur. J. Plant Pathol.,
2005, 112, 133.
19 R. Taube, Pure Appl. Chem., 1974, 38, 427.
20 On addition of NaBH4 to the reaction, the colour of the reaction
mixture changed specifically. For instance, in the reactions
catalyzed by 3a, 3b and 3c, the colour of the reaction mixture
changed to reddish brown, dark green and brown, respectively.
However, in the reduction using 3f in methanol, the colour
changed slightly to yellowish green and most of 3f remained
insoluble, showing only trace amounts of [Co(I)Pc] intermediate
formation in the reaction. The poor catalytic activity of 3f in
methanol could be attributed to its strong self-aggregation
tendency in polar solvent, which prevent its reduction to the
[Co(I)Pc] intermediate. This is in accordance with the propensity
of various functionalized phthalocyanines to form self-aggregates in
the solution phase. For details see: (a) W. J. Schutte, M. Sluyters-
Rehbach and J. H. Sluyters, J. Phys. Chem., 1993, 97, 6069;
(b) S. M. Contakes, S. T. Beatty, K. K. Dailey, T. B. Rauchfuss
and D. Fenske, Organometallics, 2000, 19, 4767; (c) M. Kimura,
H. Ueki, K. Ohta, H. Shirai and N. Kobayashi, Langmuir, 2006, 22,
5051; (d) S. Dick, H. Peisert, D. Dini, M. Hanack, M. J. Cook,
I. Chambrier and T. Chasse, J. Appl. Phys., 2005, 97, 073715.
21 (a) W. Galezowski, P. N. Ibrahim and E. S. Lewis, J. Am. Chem.
Soc., 1993, 115, 8660; (b) W. Galezowski, Inorg. Chem., 2005, 44,
1530.
22 (a) T. Okamoto, K. Kobayashi, S. Oka and S. Tanimoto, J. Org.
Chem., 1987, 52, 5089; (b) T. Okamoto, K. Kobayashi, S. Oka and
S. Tanimoto, J. Org. Chem., 1988, 53, 4897; (c) T.-H. Chao and
J. H. Espenson, J. Am. Chem. Soc., 1978, 100, 129; (d) A. von A.
Fischli and D. Suss, Helv. Chim. Acta, 1979, 62, 48; (e) A. Fischli
and J. J. Daly, Helv. Chim. Acta, 1980, 63, 1628.
23 (a) M. Takeuchi, M. Kodera, K. Kano and Z.-i. Yoshida, J. Mol.
Catal. A: Chem., 1996, 113, 51; (b) T. Okamoto and S. Oka, J. Org.
Chem., 1984, 49, 1589; (c) J.-i. Setsune, Y. Ishimaru, T. Moriyama
and T. Kitao, J. Chem. Soc., Chem. Commun., 1991, 555;
(d) T. Sugimori, S.-i. Horike, S. Tsumura, M. Handa and
K. Kasuga, Inorg. Chim. Acta, 1998, 283, 275; (e) S. Fukuzumi
and S. Noura, J. Porphyrins Phthalocyanines, 1997, 1, 251.
10 R. Mirza and R. Robinson, Nature, 1950, 166, 997.
11 G. P. Thakar, N. Janaki, B. C. Rao and Subba, Indian J. Chem.,
1965, 3, 74.
12 A. Ouchi, H. Sakai, T. Oishi, M. Kaneda, T. Suzuki, A. Saruwatari
and T. Obata, J. Photochem. Photobiol., A, 2008, 199, 261.
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Chem. Commun., 2009, 6397–6399 | 6399